The proposed studies of this Center grant are focused on basic issues concerning the pathophysiology of Parkinson's disease (PD) and their therapeutic implications. These studies are, in part, concerned with animal models of PD and key aspects of the current basal ganglia- thalamocortical circuit models of parkinsonism. Project 1 is focused on the development of a more appropriate model of PD, in particular, one that exhibits the progressive nature of PD. The proposed model employs chronic systemic inhibition of complex I by rotenone in rodents with possible extension to primates. The conceptual connective framework for projects 2-5 is the exploration and testing of the current circuit model in both animal models and patients with PD. The studies in Project 2 explore in patients with PD the effects of deep brain stimulation (DBS) of the internal pallidum (GPi) and subthalamic nucleus (TN) on behavior and brain activation of 0-15 PET. These studies will help clarify functional correlates of the amelioration of specific parkinsonian symptoms by DBS of GPi and STN. Project 3 explores, in the primate metabolism in the thalamocortical circuit using a combination of single cell recording and FDG PET. Microdialysis combined with DBS of the STN will help to clarify the mode of action of DBS. This project will also examine the potential neuroprotective effects of STN inactivation. Project 4 explores key controversial issues regarding the pathophysiology of PD using microdialysis in primates. Metabotrophic glutamate receptors are abundant in STN and GPi and specific subtypes may be promising therapeutic targets. Project 5 will test the hypothesis that specific subtypes of metabotrophic glutamate receptors may play a therapeutically relevant role in PD. The Center will also provide state-of-the-art, multi-disciplinary training of fellows in research into parkinsonism and related conditions with an emphasis on translational.